The mammalian immune system is a complex network of cells regulated by signals transmitted by many secreted and receptor proteins. The human tumor necrosis factor (TNF) superfamily includes at least 19 members and represents a major class of the stimulatory proteins. TNF-like 1A (TL1A), is a newly described member of the TNF superfamily that was shown to be involved in a range of autoimmune inflammatory diseases including inflammatory bowel diseases (IBD), Rheumatic Arthritis (RA), and Asthma. TL1A is currently the only known ligand for death-domain receptor 3 (DR3), which is predominantly expressed by activated T-cells and endothelial cells. Binding of TL1A to DR3 triggers proliferative signals probably through activation of NF-κB-associated pathways. It was shown that TL1A increases interferon (IFN)-γ production by acting in synergy with interleukin (IL)-12 and IL-18 and can thus bias the immune response towards a type 1 T helper cell (TH1) like response. It was first shown that TL1A is expressed by endothelial cells and its expression in these cells is significantly enhanced by treatments with TNF-α or IL-16. Subsequent studies have shown that TL1A is also expressed in lymphocytes plasma cells and monocytes especially in intestinal tissues from patients with inflammatory bowel diseases (IBD).
DR3, the receptor for TL1A, is expressed by CD4+ T cells and natural killer cells and its expression is increased upon T-cell activation. Although DR3 possesses an intracellular death domain that can lead to apoptosis, functional data suggest that the activity of DR3 is mainly pro-inflammatory. Interestingly, another natural receptor for TL1A is the Decoy Receptor 3 (DcR3), encoding a soluble protein that can bind TL1A with high affinity. This soluble receptor exhibit broad specificity and can bind other TNF ligands including FasL and LIGHT. Thus, it is difficult to define the contribution of DcR3 to host immunity due to the diverse functions of the three TNF ligands.
Using two distinct animal models for Chron's disease (CD) it was shown that the induction of intestinal inflammation is associated with significant up-regulation of TL1A and DR3 in the inflamed mucosa. Subsequent study using DR3 deficient mice show that DR3 expression is required on T cells for immunopathology including local T cell accumulation and cytokine production in Experimental Autoimmune Encephalomyelitis (EAE) and allergic lung inflammation disease models. Immunopathology and clinical disease were dramatically reduced in DR3 deficient mice both in mice model of lung inflammation and in EAE. In addition, it was shown that genetic variations in the TL1A gene contribute to the susceptibility to IBD in Japanese and European populations. Finally, several studies using experimental models for RA have shown that TL1A-DR3 interaction is critical for the pathogenesis of this disease.
The roles of the TL1A pathway in mediating inflammation and autoimmune disorders render it an attractive target for intervention. Blocking of TL1A binding to its endogenous DR3 receptor may lead to the abolishment of downstream signaling effects and thus prevent various inflammatory disorders.
There exists a long-felt need for more effective means of treating or ameliorating inflammatory or autoimmune diseases. The development of agents capable of inhibition of TL1A induced IFN-γ secretion is therefore desirable.